Vascular responses as therapeutic targets after SCI

内皮细胞（EC）是挫伤性脊髓损伤（SCI）后最先急性死亡的细胞之一， 继发性变性，包括轴突和髓鞘丢失。剩余的和新的血管生成血管是 渗漏和功能障碍，导致有害的白细胞浸润。我们在以下方面取得了实质性进展： 了解这些血管反应，并针对它们进行药物治疗， 神经保护例如，静脉注射Tie 2配体血管生成素-1（Ang 1）加<$v <$3/<$5 <$1 整联蛋白激动剂C16提供高水平功能恢复、血管和组织保护， 炎症成功的关键是静脉注射途径，这是快速和临床高度相关。但据 我们必须找到其他的治疗方法或目标，因为我们拯救了不到一半的血液， 血管和白色物质，无长突出下行通路。这一点至关重要， 考虑到这些以EC为靶点的治疗方法对人类的转化， 甚至远不如老鼠。我们认为，这是可能的，通过增加神经保护作用， 蛋白酪氨酸磷酸酶（PTP）抑制，其拯救通过损伤部位突出的轴突。到 目的1将确定PTP抑制是否可以 进一步增强C16+ Ang 1对EC存活和组织保护的作用，以及EC保护是否介导 拯救长突出的轴突，以及这是否涉及VE-PTP，它通常使Tie 2失活。我们有 还发现了新的途径来研究和调节血管生成，我们现在认为这是一个关键的 和对SCI的有益EC反应。我们开发了一种新的微血管纯化方法，并使用EC- 特异性微阵列，鉴定了血小板反应蛋白-1（TSP-1），一种有效的抗血管生成因子， EC凋亡，作为SCI后24小时这些血管中最高度上调的基因（60倍）。目标2将 描述了CD 36和CD 47，两种结构域特异性TSP-1 EC受体，在介导血管内皮细胞增殖中的作用。 SCI后的回复我们将在体内采取功能获得和功能丧失的药理学方法。 随后的体外实验将解决成功治疗的机制。这两个修订的目标 将确定更多的分子靶点和更好的EC靶向静脉治疗，以改善 创伤性脊髓损伤后的组织运动功能。

Endothelial cells (ECs) are among the first cells to die acutely after contusive spinal cord injury (SCI), triggering secondary degeneration, including axon and myelin loss. Remaining and newly angiogenic blood vessels are leaky and dysfunctional, enabling detrimental leukocyte infiltration. We made substantial progress in understanding these vascular responses and targeting them with pharmacological treatments for neuroprotection. For example, i.v. treatments with the Tie2 ligand angiopoietin-1 (Ang1) plus the ¿v¿3/¿5¿1 integrin agonist C16 provide high levels of functional recovery, vascular and tissue protection, and reduced inflammation. Key to the success is the i.v. route, which is rapid and clinically highly relevant. However, it is essential that we find additional therapeutic methods or targets as we rescue less than half of the blood vessels and white matter and no long-projecting descending pathways. This is critically important when considering translation of these EC-targeted treatments to humans, which do not recover neurological function even remotely as well as mice do. We suggest that this is possible by adding the neuroprotective effects of protein tyrosine phosphatase (PTP) inhibition, which rescues axons projecting through the injury site. To identify additional opportunities for neuroprotective treatments Aim 1 will determine whether PTP inhibition can further enhance the effect of C16+Ang1 on EC survival and tissue sparing and whether EC sparing mediates rescue of long-projecting axons, and whether this involves VE-PTP, which normally inactivates Tie2. We have also found new avenues to study and modulate angiogenesis, which we now recognize as one of the critical and beneficial EC response to SCI. We developed a novel microvascular purification method and using EC- specific microarrays, identified thrombospondin-1 (TSP-1), a potent anti-angiogenic factor which also induces EC apoptosis, as the most highly upregulated gene (60-fold) in these vessels 24 hours post-SCI. Aim 2 will delineate the role of CD36 and CD47, two domain-specific TSP-1 EC receptors, in mediating vascular responses after SCI. We will take both gain and loss of function pharmacological approaches in vivo. Subsequent in vitro experiments will address mechanism(s) of successful treatments. These 2 revised aims will identify additional molecular targets and much better EC-targeted intravenous treatments for improved tissue locomotor function following traumatic SCI.